Scientific Abstract Mutations in the human LMNA gene encoding lamins cause skeletal muscular dystrophy that exhibits a wide range of disease severity, even among family members possessing the identical mutation. This observation suggests the action of modifier genes. To identify candidate modifier genes, whole genome sequencing (WGS) was performed on members of a family with LMNA Emery-Dreifuss muscular dystrophy (EDMD2) (c.1580G>C; p.R527P). The analysis revealed a novel variant in the SMAD7 gene (c.932A.G; p.Q311R) that segregated with disease severity. SMAD7 encodes an inhibitor of the conserved TGF-?/Smad signaling pathway. Activation of this pathway due to reduced levels of SMAD7 represses muscle growth and differentiation and causes loss of muscle tissue homeostasis. Using a Drosophila model of LMNA muscular dystrophy, we found that over-expression of the Drosophila orthologue of SMAD7 suppressed lethality caused by mutant lamins. To test the hypothesis that Smad signaling modifies muscle phenotypes induced by mutant lamins, we will 1) alter Smad signaling and assay for effects on muscle phenotypes in Drosophila models of LMNA muscle disease and 2) perform WGS on another family with an LMNA mutation in which members exhibit either severe or asymptomatic muscle disease phenotypes. In addition, we will analyze TGF-?/Smad signaling in muscle biopsy tissue from individuals with LMNA muscular dystrophy. Collectively, our experiments will determine the interplay between TGF-?/Smad signaling and lamins in skeletal muscle disease and identify candidate modifier genes are potential targets for therapy. Our discoveries have the potential for broad impact as individuals with LMNA muscle disease have symptoms of common diseases such as diabetes and metabolic syndrome.